Epidemiological studies report increasing non-medical use and diversion of prescription opioid analgesics. Oxycodone is marketed in an array of formulations and used for the treatment of acute and chronic pain. Oxycontin(r) is a sustained-release formulation which is marketed in higher dosage formulations compared to immediate release products; both formulations have received substantial negative publicity due to reports of increased frequency of unintentional addiction, fatal overdose and criminal diversion. Hydrocodone, a related semi-synthetic opioid, is the most widely prescribed opioid analgesic in the United States and the most frequently mentioned prescription opioid in emergency room admissions. Despite their widespread clinical use, few studies have evaluated the abuse liability and clinical pharmacology of these commonly used opioids. This project will employ controlled laboratory procedures to evaluate and characterize the effects of oxycodone and hydrocodone in volunteers with histories of opioid abuse under an array of conditions. Each of the studies will use randomized, placebo-controlled, double blind, within-subject designs. Dose rising pilot evaluations will precede randomized testing for safety purposes. Experiment 1 will compare the effects of oral oxycodone and hydrocodone to those of hydromorphone, a mud opioid agonist with known high abuse potential, and placebo over a broad range of doses. Experiment 2 will focus on the sustained-release Oxycontin(r) product and will compare its pharmacokinetic and pharmacodynamic properties when administered intact or after tampering (pulverizing to by-pass the sustained release features) to immediate release oxycodone and placebo; pharmacokinetic analyses will yield bioavailability data in this study. Experiment 3 will evaluate the pharmacodynamic effects of IVoxycodone and hydrocodone compared to morphine, heroin and placebo. In all studies, data will be collected across multiple domains. Physiological and subjective measures will be collected to assess safety and abuse liability, respectively, and a battery of psychomotor and cognitive tasks will assess the impairing effects of these agents. These studies will contribute substantial new knowledge about the relative abuse potential and safety of these widely available agents at therapeutic and supratherapeutic doses in a population of subjects who are likely to abuse them. Information relevant to the public health will include the relative potency and tolerability of these compounds, the consequences of tampering with marketed formulations, and empirical information relevant to safety, scheduling and marketing of these agents.